After the Civil War began, Breckinridge was an outspoken advocate of the Confederacy. After being expelled from the Senate for his views in December 1861, he fled south and joined the Confederate Army as a general, commanding the so-called "Orphan Brigade", made up of Confederates from Kentucky. After commanding Confederate forces for most of the war, he was made Secretary of War under Jefferson Davis in 1865.

After the war ended, Breckenridge, fearing he would be charged with treason, fled, first to Cuba and then to England. In 1869, after being granted amnesty, he returned to Kentucky to practice law, and became Vice President of the Elizabethtown, Lexington, and Big Sandy Railroad Company.[1]